Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are potentially curable by hematopoietic cell transplantation (HCT). However, disease progression/relapse in patients with more advanced disease and regimen-related toxicity and transplant-related complications, in particular, graftversus- host disease (GVHD), remain problems that lead to non-relapse mortality (NRM). The use of reduced-intensity/nonmyeloablative conditioning regimens has reduced acute NRM but has not eliminated the problem of GVHD, particularly in its chronic form, and has been associated with disease progression/relapse. The overall objective of this Project is to optimize HCT strategies for patients with MDS transplanted from related or unrelated, HLA-identical or -nonidentical donors. Specifically, in Aim 1, we will carry out a multi-center, randomized prospective study comparing efficacy of myeloablative and nonmyeloablative conditioning, and determine overall survival with either approach. In Aim 2, we will conduct a pilot trial of total body irradiation (TBI) dose escalation in conjunction with fludarabine (Flu) to prevent disease progression and graft failure in patients with high-risk MDS who have not received chemotherapy before HCT. In Aim 3, we will a) determine whether reduction of the CDS cell content from GCSF mobilized peripheral blood mononuclear cells will reduce the incidence of GVHD after transplants from HLA-identical family members without increasing the risk of graft failure;b) further refine the use of in vivo T-cell depletion by Thymoglobulin in conjunction with Flu plus busulfan conditioning in patients transplanted from related or unrelated donors. In Aim 4, we will determine a) whether conditioning with Flu/TBI (+/-Campath(R)) allows for HCT from HLA class I mismatched unrelated donors;b) whether conditioning with Flu/TBI and cyclophosphamide before and after transplantation allows for HCT from haploidentical related donors. In Aim 5, we will continue long-term observation of patients with MDS who have undergone HCT to generate a database of late results. We expect these studies to provide definitive data with myeloablative as compared to nonmyeloablative HCT in comparable patient cohorts, reduce the incidence of GVHD and disease progression, broaden the indications of HCT for patients with MDS, and assess late results with HCT. Knowledge gained from these studies should allow us to offer HCT to more patients with MDS, and to improve the success rate and long-term survival.